U.S. Pat. No. 5,162,430, issued Nov. 10, 1992 to Rhee et al., and commonly owned by the assignee of the present application, discloses collagen-synthetic polymer conjugates and methods of covalently binding collagen to synthetic hydrophilic polymers. Commonly owned U.S. Pat. No. 5,292,802, issued Mar. 8, 1994, discloses methods for making tubes comprising collagen-synthetic polymer conjugates. Commonly owned U.S. Pat. No. 5,306,500, issued Apr. 26, 1994, discloses methods of augmenting tissue with collagen-synthetic polymer conjugates.
Commonly owned U.S. Pat. No. 5,328,955, issued Jul. 12, 1994, discloses various activated forms of polyethylene glycol and various linkages which can be used to produce collagen-synthetic polymer conjugates having a range of physical and chemical properties. Commonly owned, copending U.S. application Ser. No. 07/984,933, filed Dec. 2, 1992, discloses methods for coating implants with collagen-synthetic polymer conjugates.
Commonly owned, copending U.S. application Ser. No. 08/146,843, filed Nov. 3, 1993, discloses conjugates comprising various species of glycosaminoglycan covalently bound to synthetic hydrophilic polymers, which are optionally bound to collagen as well. Commonly owned, copending U.S. application serial No. 08/147,227, filed Nov. 3, 1993, discloses collagen-polymer conjugates comprising chemically modified collagens such as, for example, succinylated collagen or methylated collagen, covalently bound to synthetic hydrophilic polymers to produce optically clear materials for use in ophthalmic or other medical applications.
Commonly owned U.S. application Ser. No. 08/236,769, filed May 2, 1994, discloses collagen-synthetic polymer matrices prepared using a multiple step reaction.
All publications cited above and herein are incorporated herein by reference to describe and disclose the subject matter for which it is cited.
In our earlier issued patents and applications described above, we disclosed biomaterial compositions comprising collagen or other biocompatible polymers crosslinked using synthetic hydrophilic polymers. These crosslinked compositions were generally prepared by mixing aqueous suspensions of collagen or biocompatible polymers with aqueous solutions of synthetic hydrophilic polymers. The resulting crosslinked biomaterial compositions could be used in a variety of medical applications, such as soft tissue augmentation and the preparation of biocompatible implantable devices.
Unfortunately, there was a major drawback to the method of preparing crosslinked biomaterial compositions described above: synthetic hydrophilic polymers, such as functionally activated polyethylene glycols, are highly reactive with water, as well as with collagen and other polymers having corresponding reactive groups such as, for example (and not by way of limitation), available amino groups. The longer the synthetic hydrophilic polymer is exposed to water (or water-based carriers), the more of its activity is lost due to hydrolysis, resulting in partial to complete loss of crosslinking ability. Therefore, in order to avoid significant loss of crosslinking activity due to hydrolysis, the synthetic hydrophilic polymer must be thoroughly mixed with an aqueous carrier to prepare a homogeneous, aqueous crosslinker solution immediately prior to being mixed with an aqueous suspension of collagen (or other suitable biocompatible polymer) to prepare a crosslinked biomaterial composition. Unfortunately, a certain amount of activity could still be expected to be lost, despite the speed of the operator preparing the composition.
While the above method for preparing crosslinked biomaterials compositions had its drawbacks with respect to preparing formed implants, it represented an even greater hurdle in the development of a viable commercial product for use in tissue augmentation. For example, the synthetic hydrophilic polymer could not be stored in an aqueous state because it would hydrolyze, nor could it be stored mixed with the collagen because the two components would react and form a non-extrudable gel within the syringe. Therefore, the synthetic hydrophilic polymer needed to be provided to a physician in dry form, then dissolved in an aqueous carrier immediately prior to mixing with the collagen suspension. The contemplated method required a number of preparatory steps that needed to be performed in rapid succession by the physician in order to provide successful tissue augmentation. In other words, the suggested process was cumbersome and certainly not "user friendly".
In the contemplated method, the physician would be provided with a syringe containing an appropriate amount of an aqueous carrier solution, such as phosphate-buffered saline (PBS), a vial containing an appropriate amount of a dry crosslinking agent, such as a synthetic hydrophilic polymer, and a relatively large-gauge needle, such as a 20-gauge needle. Prior to mixing the crosslinking agent with the collagen (which would be provided in its own syringe), the physician would need to perform the following steps: 1) unwrap the package containing the needle; 2) remove the cap from the syringe containing the aqueous carrier; 3) attach the needle to the syringe; 4) dispense the aqueous carrier by means of the needle into the vial containing the dry crosslinking agent; 5) vortex or otherwise adequately mix the crosslinking agent with the aqueous carrier within the vial to produce an aqueous crosslinker solution (which has already started to hydrolyze in the presence of water); 6) withdraw the crosslinker solution into the syringe; and 7) remove the needle from the syringe in preparation for mixing the crosslinker solution with the collagen (or other biomaterial). All of these preparatory steps would need to be performed within minutes of mixing the crosslinker solution with the collagen and injecting the patient in order to minimize loss of crosslinker activity.